A Dose Escalation and Cohort Expansion Study of NKTR-214 in Combination With Nivolumab and Other Anti-Cancer Therapies in Patients With Select Advanced Solid Tumors ( PIVOT-02 ) (PIVOT-02)

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In this four-part study, NKTR-214 will be administered in combination with nivolumab in Part 1, in combination with nivolumab with or without various chemotherapies in Part 2, and with nivolumab and ipilimumab in Parts 3 & 4. In Part 1, the Recommended Phase 2 Dose (RP2D) of NKTR-214 in combination with nivolumab will be determined. In Part 2, NKTR-214 with nivolumab at the RP2D will be evaluated as first-line therapy and/or as second or third line therapy in select patients with Melanoma, Renal Cell Carcinoma (RCC), Non-Small Cell Lung Cancer (NSCLC), Urothelial Carcinoma (UC), metastatic Breast Cancer (mBC) and Colorectal Cancer (CRC). In addition, in Part 2, the RP2D of NKTR-214 with nivolumab and various chemotherapies and regimens in select cohorts of NSCLC patients will be determined. In Part 3, several different regimens of the triplet combination of NKTR-214 plus nivolumab and ipilimumab will be evaluated in select patients with RCC, NSCLC, Melanoma, and UC. In Part 4, the safety and efficacy of the triplet combination will be evaluated further in select patients with RCC, NSCLC, Melanoma and UC.

NKTR-214 (investigational agent) is an IL-2 pathway agonist designed to target CD122, a protein which is found on certain immune cells (known as CD8+ T Cells and Natural Killer Cells) to expand these cells to promote their anti-tumor effects. Nivolumab is a full human monoclonal antibody that binds to PD-1 (programmed cell death protein 1) on immune cells and promotes anti-tumor effects. NKTR-214, nivolumab and ipilimumab each target the immune system differently and may act synergistically to promote anti-cancer effects.

The study is designed in four parts.

Part 1: Dose escalation of NKTR-214 in combination with nivolumab. Part 1 has been completed and the recommended phase 2 dose (RP2D) has been identified, which is being studied further in Parts 2, 3 and 4 of the study.

Part 2: Dose expansion of NKTR-214 in combination with nivolumab. Patients with the following tumor types (Melanoma, RCC, NSCLC, UC, mBC and CRC) will be enrolled to receive the RP2D of NKTR-214 in combination with nivolumab. In addition, NKTR-214 with nivolumab and other anti-cancer therapies including cytotoxic chemotherapy will be evaluated in select patients with NSCLC. Each cohort in Part 2 has a target enrollment of 12-36 patients and could include up to a total of 650 patients who are either checkpoint-therapy naïve or anti-PD-1 or anti-PD-L1 relapsed/refractory. One dedicated and separate cohort in Part 2 will evaluate NKTR-214 with nivolumab in an additional 100 second-line NSCLC patients previously treated with an anti-PD-1 or anti-PD-L1 in combination with doublet platinum-containing cytotoxic chemotherapy in first-line.

Part 3: Schedule and safety finding of NKTR-214 in combination with nivolumab and ipilimumab. During this part of the study, the RP2D triplet combination schedules will be determined in the following tumor types: RCC, NSCLC, Melanoma, or UC.

Part 4: Dose expansion of triplet combinations of NKTR-214 in combination with nivolumab and ipilimumab in select tumor types. Each cohort will enroll between 6-36 patients and could include up to 106 patients. Enrollment into Part 4 will commence once the RP2D for the triplet combination has been established in Part 3 for each respective tumor type.

All patients enrolled in the study will be closely monitored for safety, tolerability and response per RECIST criteria. The primary efficacy endpoint of the combination will be assessed using objective response rate (ORR). Exploratory immunological biomarkers in plasma and tumor samples will evaluate immune activation.

A Phase 1/2, Open-label, Multicenter Study of the Combination of NKTR-214 and Nivolumab or the Combination of NKTR-214, Nivolumab, and Other Anti-Cancer Therapies in Patients With Select Locally Advanced or Metastatic Solid Tumor Malignancies

Efficacy of NKTR-214 in combination with nivolumab as assessed by the Objective Response Rate (ORR) based on immune-related RECIST (irRECIST) at the RP2D. [ Time Frame: Through study completion, an expected average of 2 years ]

Efficacy of NKTR-214 in combination with nivolumab and ipilimumab as assessed by the Objective Response Rate (ORR) based on immune-related RECIST (irRECIST) at the RP2D. [ Time Frame: Through study completion, an expected average of 2 years ]

Secondary Outcome Measures :

Overall Survival (OS) [ Time Frame: Within 3 years from study start ]

Overall survival is defined as the time from date of first dose to the date of death

Progression-Free Survival (PFS) [ Time Frame: Through study completion, an expected average of 2 years ]

PFS is defined as the time from date of first dose to the date of the first objectively documented tumor progression or death due to any cause.

CBR will be assessed as the number of subjects with a BOR of Complete Response (CR), confirmed Partial Response (PR), or Stable Disease (SD) (where the duration of SD should be ≥ 84 days) divided by the total number of subjects in the Response Evaluable Population

Duration of Response (DOR) [ Time Frame: Through study completion, an expected average of 2 years ]

DOR is defined as time between the date of first radiographic images that documented objective response and the date of the first radiographic images that documented disease progression.

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Layout table for eligibility information

Ages Eligible for Study:

18 Years and older (Adult, Older Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

INCLUSION CRITERIA - For Parts 1-4:

Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) or metastatic solid tumors

Use of an investigational agent or an investigational device within 28 days before administration of first dose of NKTR--214

Females who are pregnant or breastfeeding

Participants who have an active autoimmune disease requiring systemic treatment within the past 3 months or have a documented history of clinically severe autoimmune disease that requires systemic steroids or immunosuppressive agents

History of organ transplant that requires use of immune suppressive agents

Participants who have had < 28 days since the last chemotherapy, biological therapy, or < 14 days from approved tyrosine kinase inhibitor (TKI) therapy, or systemic or inhaled steroid therapy at doses greater than 10mg of prednisone Tumor specific exclusion criteria may apply.